The long term objective of this program is to elucidate the intrinsic regulatory mechanisms that control the structure and function of the resilient layer of articular cartilage that covers and protects the ends of bone. We showed that TGF-beta has the ability to prevent the spontaneous proteoglycan loss that occurs in basal cartilage organ cultures by increasing biosynthetic rates and decreasing degradation. We proposed that TGF-beta is an intrinsic modulator of cartilage proteoglycan metabolism and obtained a line of evidence to support this hypothesis. For example, we showed that TGF-beta is a strong antagonist of the most powerful known resorptive agent for cartilage, retinoic acid. This vitamin increases catabolism and depresses rates of re-deposition. In the original experiments, the two signaling factors were added together to the cartilage explants. We have now modified our protocols to ask whether TGF-beta is an effective repair agent following retinoic acid treatment. After a week of treatment with retinoic acid, proteoglycan synthesis falls to approximately 10% of controls and recovery following removal of the retinoid from the medium is inadequate (an average 2-fold increase over retinoid treated samples). Recovery is greatly improved by TGF-beta (10-20 fold increase). However, the rates of synthesis in the presence of TGF-beta following retinoid exposure never reach the levels of control cultures treated with the cytokine. The effect of IGF-1 mirrors that of TGF-beta. However, when both TGF- beta and IGF-1 are added to the recovering cultures, the anabolic rates rise to levels comparable to those of similarly treated control cultures. Our studies have uncovered an additive response between TGF-beta and IGF- 1 and indicated that this interaction should be taken into account for the future design of in vivo repair treatments following matrix injury, such as occurs during osteoarthritis.